The devastation of Alzheimer's dementia costs $100 billion today and will economically cripple American health care if not controlled in the next decade. Pathology and genetic studies indicate the accumulation of the Aa peptide as a major precipitating factor in the disease. Multiple strategies using traditional small molecule drugs to arrest this accumulation are being investigated, but, thus far, success remains elusive. One;problem is that systemic application of many agents have unintended consequences outside the brain. Even the anti-Aa vaccines had to be halted due to unforeseen, serious adverse events. This application proposes a relatively new approach to lowering brain Aa by exploiting gene therapy to enhance the clearance and reduce the production of Aa. The approach will inject recombinant acieno-associated viral vectors (rAAV), known to safely result in stable neuronal expression of transduced genes, into APP+P81 transgenic mice, which reliably deposit a amyloid and develop learning and memory deficits. rAAV vectors transferring proteases to degrade Aa or transferring inhibitory RNA constructs against enzymes producing Aa will be injected into the hippocampus and cerebral cortex. Their efficacy and safety of these vectors will be tested in young mice, to evaluate their capacity as prophylactic treatments and in older mice to estimate their potential utility as therapeutics. Additionally, we will investigate multiple methods for maximizing the distribution of transferred genes throughout the nervous system. The rAAV construct with therapeutic efficacy, optimal safety and broad distribution will be selected for further development as a treatment for Alzheimer's. The outcome of these studies will, hopefully, be a novel gene therapeutic approach to dismantle the catastrophe of Alzheimer's dementia.